The main goal of the proposed research is to determine how the pharmacologic actions of nicotine and the sensory/behavioral aspects of cigarette smoking contribute to tobacco dependence. In the proposed work, the pharmacologic effects of smoking will be delivered using intravenous (i.v.) nicotine infusions; conversely, the non-nicotine components of the smoking habit will be conveyed using de-nicotinized cigarettes. By dissociating and independently varying these two key components, we will gain a better understanding of the reinforcement processes maintaining smoking behavior. Laboratory studies will assess the determinants of nicotine self-administration and preference between nicotine and non-nicotine components of cigarette smoke. We will measure how preference for nicotine is affected by nicotine replacement in the form of nicotine skin patches. The ability of nicotine and non- nicotine smoke components to satiate smoking behavior will also be assessed. The relative roles of peripheral and central nervous system nicotinic receptors will be examined using different nicotinic antagonists. In addition to participating in the laboratory studies, subjects will be able to enroll in a smoking cessation program using nicotine skin patch therapy. Responses to i.v. nicotine and to the sensory/behavioral cues in the laboratory studies will be correlated with the clinical response to nicotine replacement treatment. The results will lead to a better understanding of the role of pharmacologic and sensory/behavioral cues in nicotine addiction and smoking cessation.